We have considered a rather wide-ranging number of genotropic theories of aging, defined as those which specify genomic alterations as the key to the understanding of the mechanisms of senescence. The fifteen ideas we have discussed are listed in Table 1, which divides them, in a rather arbitrary fashion, into two broad classes--those which emphasize modifications in gene structure and those which emphasize modifications in gene expression. It seems probable that no single one of these ideas will emerge as "the" underlying mechanism of aging, but that many of them will prove to have some credence. The aging process most certainly is under highly polygenic controls. In the case of human beings, I have made crude estimates [33] based upon a analysis of the phenotypes of known or suspected alleles at 2,336 genetic loci and the assumption of an upper limit for man of 100,000 informational loci, that anywhere from about 70-7000 genes could in fact be involved. This should not discourage us from pursuing a search for those loci which may be of profound importance to human aging as it ordinarily occurs in most human beings. In my opinion, however, the most pressing short-term need for biomedical gerontologists is to discover biochemical genetic reasons to explain why certain individuals seem especially prone to one or another of the age-related debilities, such as cancer, the various forms of arteriosclerosis, diabetes mellitus, osteoporosis, osteoarthritis, senile cataracts and senile dementia. Therefore, in my view, the future of progress in geriatric medicine is likely to be closely coupled to progress in medical genetics and genetic pathology.
There is little doubt that aging changes occur in specific brain cells and neural pathways. Since some of these changes occur in short-lived rodents which probably have no major vascular pathology [48], there may be a general phenomenon of aging in the brain neurotransmitter functions in short- and long-lived mammals. It remains to be discovered how the genome regulates the changes in catecholamine neurotransmitter functions and, further, how these changes relate to normal and pathologic age changes.
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